Aromatic compounds, especially naphthalene derivatives, bearing fluorine atoms on adjacent carbons (i.e., vicinal) have been found to be useful as liquid crystal materials. They are typically made by a multi-step process, starting from the aromatic amine via a fluoro-dediazoniation process (N. Yoneda and T. Fukuhara, Tetrahedron, vol. 52, No. 1 (1996), pages 23-36).
No simple methods are known for producing vicinal difluoro aromatic compounds. Methods for defluorinating highly fluorinated compounds are known; but, none of the methods have been shown to produce vicinal difluoro compounds in high yield. For example:
C. Hu, et al., Journal of Fluorine Chemistry, Vol. 48 (1990), pages 29-35, disclosed a method of synthesizing perfluoroaromatics, such as tetradecafluorobicyclo[4.4.0]dec-1(2),6(7)-diene and perfluorotetralin, by defluorination of hexadecafluorobicyclo[4.4.0]dec-1(6)-ene in an aprotic solvent using activated zinc powder as a catalyst. The extent of defluorination depended on the polarity of the aprotic solvent used.
J. Burdon and I. W. Parsons, Journal of Fluorine Chemistry, Vol. 13 (1979), pages 159-162, disclose the formation of 2,5-difluorothiophen by pyrolysis of 2,2,5,5-tetrafluoro-3-thiolen over sodium fluoride.
Sergey S. Laev and Vitalii D Shteingarts, Journal of Fluorine Chemistry, Vol. 96 (1999) pages 175-185, disclose the reductive dehalogenation of polyfluoroarenes by zinc in aqueous ammonia. In the reaction, hydrogen atoms replace fluorine atoms in the polyfluoroarenes.
JP 2001-10995A (Ogawa, et al.) describes a four-step process for synthesis of vicinal difluoro aromatic compounds involving fluorination of a hydroxy aromatic compound to form a tetrafluoro intermediate in two steps followed by hydrogenation and defluorination under basic conditions. It also discloses reduction of a difluoroketone intermediate with aluminum isopropoxide and then base-catalyzed dehydrohalogenation to form a difluoro aromatic compound. A third method involves reaction of the difluoroketone with lithium aluminum hydride to form a fluoroepoxide, addition of HF, and elimination of water to give a vicinal difluoro aromatic compound. The best overall yield shown is  less than 50%.
There remains a need for an effective and simple method for preparing vicinal difluoro aromatic compounds in high yield.
This invention is directed to a method of preparing vicinal difluoro aromatic compounds in high yield from hydroxy aromatic compounds and to preparing intermediates thereof. The hydroxy aromatic compound can be a mono-, bi- or tricyclic aromatic in which the rings are separate or fused. One or more of the rings can contain heteroatoms, such as oxygen, nitrogen, or sulfur, and can contain substitutions, in addition to the hydroxy substitution. Substitutions on one or more of the rings can include a halogen atom, a C1 to C20 alkyl, a C5-C10 cycloalkyl, a C6 to C12 aryl, an amino, a nitro, a C1 to C10 alkyl ether or thioether, a C1 to C10 alkyl ester, a CF3, a Rxe2x80x2SO2O, 
where Rxe2x80x2 is CF3, a C1 to C20 alkyl, a substituted or unsubstituted C5 to C10 cycloalkyl, or a substituted or unsubstituted C6 to C12 aryl, in which the substitution on the cycloalkyl or aryl can be a C1 to C20 alkyl or a C5 to C8 cycloalkyl; Rxe2x80x3 is a C1-C10 saturated or unsaturated alkyl; x is an integer from 0 to 10, and y is an integer from 0 to 10.
The process can be described by the following reaction steps: 
where R is a hydrogen atom, a halogen atom (Cl, Br, I, F), Rxe2x80x2SO2O, CF3, a fused aryl, a C1-C20 alkyl, amino, nitro, a C1 to C10 ether or thioether, a C1 to C10 ester, a heteroaryl, wherein the heteroatom can be O, N, S, 
or R forms an aryl. Rxe2x80x2 is CF3, a C1 to C20 alkyl, a substituted or unsubstituted C5 to C10 cycloalkyl, or a substituted or unsubstituted C6 to C12 aryl, wherein the substitution on the cycloalkyl or aryl can be a C1 to C20 alkyl or a C5 to C8 cycloalkyl; Rxe2x80x3 is a C1-C10 saturated or unsaturated alkyl; x is an integer from 0 to 10, and y is an integer from 0 to 10. The preferred R group is trans-4-propylcyclohexyl.
The yields obtained from reactions (1) and (2) are highly dependent on the solvents employed for these steps. Polar aprotic solvents are desirable for the electrophilic fluorination in step (1) and dimethylformamide (DMF) is particularly preferred because it unexpectedly resulted in yields of greater than 95% difluoro ketone product. Reaction step (2) can be conducted in various solvents including aliphatic and aromatic hydrocarbons, halocarbons, ethers, etc.; however, toluene unexpectedly gives much higher yields of the tetrafluoro product compared to other organic solvents. Step (3) involves reacting the tetrafluoro compound with a reducing agent, such as metallic zinc, copper, magnesium, or a mixture thereof, to form the vicinal difluoro aromatic compound in high yields (e.g., 90% or more). This reaction is preferably carried out in buffered aqueous ammonia in the presence of an organic solvent such as tetrahydrofuran (THF), methyl tert-butyl ether, acetonitrile, ethanol, or DMF. Since the tetrafluoro compound reacts under basic conditions to form a trifluoronaphthalene by-product, the pH of the aqueous ammonia is buffered to  less than 14 by addition of an ammonium salt, particularly NH4Cl. Under these conditions, the selectivity to the desired vicinal difluoronaphthalene product is significantly increased.
This method of preparing vicinal difluoro aromatic compounds has the following advantages over known methods:
the difluoro ketone and tetrafluoro intermediates do not need to be purified prior to subsequent reaction,
the product is produced in high selectivity,
the overall yield is 70% or more, and
the product easily can be separated and purified by known methods.
In the method of this invention, vicinal difluoro aromatic compounds can be prepared in three steps from hydroxy aromatic compounds by electrophilic fluorination using a fluorination reagent such as Selectfluor(copyright) reagent (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis-tetrafluoroborate) to form a difluoroketone intermediate. The difluoro ketone undergoes nucleophilic fluorination by reaction with a deoxofluorinating reagent such as Deoxo-Fluor(copyright) reagent (bis(2-methoxyethyl)-aminosulfur trifluoride) to give a tetrafluoro intermediate species. The tetrafluoro intermediate is defluorinated by a metallic reducing agent in the presence of ammonium hydroxide, preferably buffered ammonium hydroxide, to provide the desired vicinal difluoro aromatic compound in high yield. An example of the reaction chemistry is described above in the Brief Summary of the Invention.
In the first step, a hydroxy aromatic compound (e.g., xcex2-naphthol or substituted naphthol) is reacted with an electrophilic fluorinating agent such as Selectfluor reagent, to generate a difluoroketone intermediate. This reaction can be conducted in various solvents including nitrites such as acetonitrile (CH3CN), formamides such as dimethylformamide (DMF), CH3NO2, carboxylic acids such as acetic acid, water, and an alcohol such as methanol, ethanol, and propanol.
The reaction can be carried out at temperatures ranging from 0xc2x0 C. to the boiling point of the solvent.
The fluorinating agent can be added to a solution or suspension of the hydroxy aromatic compound in one or more portions, or dropwise as a solution. Alternatively, the hydroxy aromatic compound solution or suspension can be added to a solution or suspension of fluorinating agent.
In the second step, the carbonyl oxygen of the difluoroketone is replaced by two fluorine atoms using a deoxofluorinating agent such as Deoxo-Fluor reagent. The reaction is carried out by reacting the difluoroketone with the deoxofluorinating agent in an organic solvent in an anhydrous atmosphere. Solvents include alkanes such as hexane, heptane, etc.; aromatic hydrocarbons such as toluene, xylenes, etc.; haloalkanes such as methylene chloride, chloroform, etc.; ethers, such as diethyl ether, THF, etc.; and any other solvent that will not react with the fluorinating reagent.
The reaction temperature can range from 0xc2x0 C. to 90xc2x0 C. In carrying out the reaction, the difluoroketone can be mixed with the entire charge of the fluorinating reagent or the reagent can be added dropwise to a solution of the difluoroketone. Lewis acid catalysts such as boron trifluoride etherate (BF3.Et2O) or HF can be used to accelerate the reaction. The product obtained is usually a mixture of the desired 1,1,2,2-tetrafluoro compound and the corresponding 1,1,2,4-tetrafluoro isomer. We have found that both the yield and the isomer ratio are highly dependent on the solvent used. Toluene is unexpectedly superior to other organic solvents in producing a high yield of the desired isomer. For example, when THF was used as solvent at 60xc2x0 C., a 65% yield of 1,1,2,2-tetrafluoro-6-trans-4-propylcyclohexyl)-1,2-dihydronaphthalene was obtained (1,1,2,2-tetrafluoro/1,1,2,4-tetrafluoro=51/49), while when toluene was used as solvent at the same temperature, an 85% yield was obtained (1,1,2,2-tetrafluoro/1,1,2,4-tetrafluoro=90/10) under the same reaction conditions.
In the third step of the process, the mixture of tetrafluoro isomers is reductively defluorinated using a reducing agent in an aqueous ammonia solution, preferably a buffered aqueous ammonia medium. Both tetrafluoro isomers react to form the same vicinal difluoro aromatic product.
The reducing agent in this method can be metallic zinc or other known reducing agents, such as copper, magnesium, or mixtures thereof. The metals typically are used in powder form, but other forms should also be effective. Reducing agents that do not react rapidly with water are preferred. At least one molar equivalent of the reducing agent, based on the amount of starting compound, is needed.
The process of reductive defluorination is preferably carried out in buffered aqueous ammonia with an organic co-solvent, such as THF. The organic co-solvent can be used to make a solution of the tetrafluoro aromatic compound. Other co-solvents that can be used include ethers such as methyl tert-butyl ether; nitrites such as acetonitrile; alcohols such as ethanol; and amides such as DMF. The aqueous ammonia is buffered to a pH  less than 14 and preferably  less than 11 with an ammonium salt; preferably ammonium chloride. Maintaining a pH below 14, minimizes the production of unwanted by-products. For example, when the reaction medium is too basic (i.e., a pH of 14), 1,1,2,2-tetrafluoro dihydronaphthalene is converted to a 1,2,4-trifluoronaphthalene compound as shown in the reaction below: 
The rate of this reaction has been found to be pH-dependent, and consequently the selectivity to this impurity is significantly reduced as the pH is reduced below 14, especially below 11.
Typically 3.2 ml of ammonium hydroxide and 1.6 ml of organic solvent per mmol of starting compound are appropriate for the reaction.
The reaction can be carried out at temperatures ranging from 0xc2x0 C. to the boiling point of the solvent; preferably 25 to 45xc2x0 C.
The reaction can be run in air or more preferably under an inert gas, such as nitrogen.
The reaction can be monitored by methods known in the art to determine completion. For example GC or GC/MS (gas chromatography/mass spectrometry) can be used to determine when the reaction is complete. Reaction times typically range from 2-48 hours.
The vicinal difluoro aromatic product can be isolated from the reaction mixture by methods known in the art. For example, the product can be isolated by filtering the reducing metal, extracting the aqueous layer into an immiscible organic solvent, evaporating the solvent, and purifying the product using chromatography, distillation, and/or recrystallization.
The invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the invention.